Enhanced activity of apramycin and apramycin-based combinations against Mycobacteroides abscessus

Mycobacteroides abscessus is a rapidly growing non-tuberculous mycobacterium that causes chronic lung and soft tissue infections. Treatment options are severely limited. Amikacin has historically been a mainstay of combination treatment regimens. However, irreversible hearing loss and vestibular toxicity have led to a search for alternative agents. Apramycin is a novel aminoglycoside currently in Phase I clinical trials that may offer lower potential for ototoxic and renal toxic side effects.

The goal of this study was to compare apramycin's in vitro activity with amikacin and other aminoglycosides against a large collection of M. abscessus clinical isolates, alone, and for apramycin and amikacin, in combination with clofazimine or linezolid. We also examined activity against a more limited collection of other rapidly growing mycobacteria.

Analysis was performed using reference broth microdilution MIC testing, inkjet printer-assisted checkerboard assays, and time-kill assays.

Against M. abscessus, the MIC50/90 for apramycin (2 mg/L) was one-eighth that of amikacin (16 mg/L). Plazomicin was inactive, and organisms were rarely susceptible to tobramycin. Synergy of either apramycin or amikacin with clofazimine or linezolid was not detected by checkerboard assay. In time-kill studies, clofazimine modestly increased activity of apramycin and, to a lesser extent, amikacin. Apramycin and amikacin showed delayed bacterial killing that either achieved or approached a bactericidal threshold. Apramycin was similarly potent against other rapidly growing mycobacteria tested.

Apramycin exhibits more potent in vitro activity against a diverse set of M. abscessus and other rapidly growing mycobacteria than currently recommended aminoglycosides.